Depletion of tropomyosin 1.6 alleviates TGF-β1-induced fibroblast activation by promoting the α-SMA-MMP9 matrix-degrading structure.

Fibroblasts can be transformed into myofibroblasts under pro-fibrotic conditions, which are characterized by increased contractility and reduced matrix degradation. The relationship between contractile activity and matrix degradation is not fully understood. To mimic physiological conditions, fibroblasts were cultured on a collagen gel with low rigidity. We reveal that a tropomyosin isoform, tropomyosin 1.6 (Tpm1.6), plays a pivotal role in the phenotypic switch upon TGF-β1. Tpm1.6 was specifically upregulated by TGF-β1 in renal fibroblasts. Tpm1.6-silencing decreased TGF-β1-induced myofibroblast markers and contractility, and promoted collagen degradation. Remarkably, in Tpm1.6-silenced fibroblasts, TGF-β1 triggered the formation of distinct α-SMA dots enriched with MMP9, promoting collagen degradation. The targeted silencing of Tpm1.6 in activated myofibroblasts by the induction of promoters of Foxd1 and Acta2 mitigated unilateral ureteral obstruction-induced renal fibrosis and preserved proximal tubule differentiation. Our study highlights the crucial role of Tpm1.6 in TGF-β1-induced myofibroblast activation and collagen degradation, suggesting a potential therapeutic approach for chronic kidney disease.